Brain delivery of nipecotic acid by the administration of its ester prodrug via the nasal route

(±)-Nipecotic acid is one of the most potent and selective in-vitro inhibitors of the GABA re-uptake system. Nipecotic acid's potential clinical value resides with its utility in the treatment of neurological disorders associated with GABA deficiencies, such as epilepsy, pain, and anxiety. Unfortunately, nipecotic acid is a zwitterion that does not easily penetrate the blood brain barrier. The prodrug approach has been used to facilitate the brain delivery of nipecotic acid. However, the practical utility of these prodrugs has been limited by the requirement that drug administration utilize the invasive iv route. The purpose of this research was to determine if the nasal route would be an acceptable alternative to the iv route for the administration of a nipecotic acid ester prodrug.; After the butyl ester was identified as the most viable nipecotic acid prodrug for nasal formulation, both nipecotic acid and the butyl ester were administered to rats intravenously and intranasally. It was found that the systemic availability of nipecotic acid was enhanced substantially by nasal administration of its butyl ester relative to nipecotic acid. Nasal administration of the ester prodrug provides a rapid and complete absorption of the butyl ester, which is comparable to that after iv administration. The different pharmacokinetics of nipecotic acid resulted following nasal and iv administration of the butyl ester suggests possible tissue trapping of nipecotic acid after the administration of the butyl ester.; The administration of the butyl ester produced peak nipecotic acid levels in the brain at 10 min, and the concentration-time profiles of nipecotic acid in brain were superimposable after nasal and iv administration of its butyl ester. This suggests: (1) the nasal route provides a brain delivery for nipecotic acid that is as good as an iv injection of the ester; (2) administration of the butyl ester should result in a quick onset of action for nipecotic acid.; In conclusion, the butyl ester of nipecotic acid can deliver nipecotic acid to the brain, and the nasal administration of the prodrug is a convenient and effective method for its brain delivery. The availability of a pharmaceutical nasal dosage form of this prodrug might be of value for nipecotic acid self-administration for treating epileptic seizure, neuropathic pain and/or anxiety in outpatient settings.